Cardiac mitochondrial function is altered in a variety of inherited and acq
uired cardiovascular diseases. Recent studies have identified the transcrip
tional coactivator peroxisome proliferator-activated receptor gamma coactiv
ator-1 (PGC-1) as a regulator of mitochondrial function in tissues speciali
zed for thermogenesis, such as brown adipose. We sought to determine whethe
r PGC-1 controlled mitochondrial biogenesis and energy-producing capacity i
n the heart, a tissue specialized for high-capacity ATP production. We foun
d that PGC-1 gene expression is induced in the mouse heart after birth and
in response to short-term fasting, conditions known to increase cardiac mit
ochondrial energy production. Forced expression of PGC-1 in cardiac myocyte
s in culture induced the expression of nuclear and mitochondrial genes invo
lved in multiple mitochondrial energy-transduction/energy-production pathwa
ys, increased cellular mitochondrial number, and stimulated coupled respira
tion. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted
in uncontrolled mitochondrial proliferation in cardiac myocytes leading to
loss of sarcomeric structure and a dilated cardiomyopathy. These results id
entify PGC-1 as a critical regulatory molecule in the control of cardiac mi
tochondrial number and function in response to energy demands.